Fe-S Cluster Biogenesis in Gram-Positive Bacteria: SufU Is a Zinc-Dependent Sulfur Transfer Protein

Selbach, Bruna Pelegrim; Chung, Alexander H.; Scott, Aubrey D.; George, Simon J.; Cramer, Stephen P.; Santos, Patricia C. Dos

doi:10.1021/bi4011978

Cited by 68 publications

(102 citation statements)

References 42 publications

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“…5), whereas, in the absence of ATP, MnmA did not affect YrvO's cysteine desulfurase activity. This activity enhancement has also been observed for cysteine desulfurases in the presence of their corresponding sulfur acceptors and has been attributed to the ability of sulfur acceptor substrates to accelerate the regeneration of the enzyme for the next catalytic cycle through a rapid persulfide sulfur transfer (19,20,30,31). That is, the sulfur transfer step from YrvO to MnmA is faster than the reduction of YrvO's persulfide by DTT.…”

Section: Levels Of Expression Of Mnma Affects Abundance Of Smentioning

confidence: 58%

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Abbreviated Pathway for Biosynthesis of 2-Thiouridine in Bacillus subtilis

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Santos

2015

J Bacteriol

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The 2-thiouridine (s 2 U) modification of the wobble position in glutamate, glutamine, and lysine tRNA molecules serves to stabilize the anticodon structure, improving ribosomal binding and overall efficiency of the translational process. Biosynthesis IMPORTANCEThe 2-thiouridine (s 2 U) modification of the wobble position in glutamate, glutamine, and lysine tRNA is conserved in all three domains of life and stabilizes the anticodon structure, thus guaranteeing fidelity in translation. The biosynthesis of s 2 U in Escherichia coli requires seven proteins: the cysteine desulfurase IscS, the thiouridylase MnmA, and five intermediate sulfur-relay enzymes (TusABCDE). Bacillus subtilis and most Gram-positive bacteria lack a complete set of biosynthetic components. Interestingly, the mnmA coding sequence is located adjacent to yrvO, encoding a cysteine desulfurase. In this work, we provide evidence that the B. subtilis YrvO is able to transfer sulfur directly to MnmA. Both proteins are sufficient for s 2 U biosynthesis in a pathway independent of the one used in E. coli. P osttranscriptional RNA modifications are found among all organisms and are essential for their cellular function. More than 100 RNA modifications have been identified thus far which have a variety of physiological functions (1). In particular, posttranscriptional modifications of tRNA are often necessary for translational fidelity and efficiency, especially those found in anticodon bases. The third base in the anticodon is deemed the wobble position, as it is bound more loosely to the ribosome than the first two. Consequently, wobble bases have greater flexibility, allowing them to make noncanonical base pairs, leading to a greater chance of amino acid misincorporation into a growing peptide chain. An explanation of how this phenomenon is overcome is provided by the modified wobble hypothesis, which states that certain base modifications have evolved to adjust the anticodon shape, either to limit or to enable the occurrence of wobble pairing (2).The modification of the wobble (34th position) in glutamate (Glu), glutamine (Gln), and lysine (Lys) tRNA molecules produces 5-methyl-2-thiouridine derivatives (xm 5 s 2 U) (Fig. 1). Thiolation of the wobble uridine places the base in an anti, C-3=-endo, gauche conformation, thus forming a rigid structure, which increases its affinity for pairing with adenosine and thereby yields higher accuracy in the corresponding peptide sequence. Additionally, this modification stabilizes the anticodon structures and confers the tRNA molecule's ability to bind to the ribosome. Tighter ribosomal binding to tRNA subsequently improves reading frame maintenance and deficiencies in the translational process (2-5). Lack of the 2-thiouridine (s 2 U) modification in tRNA causes growth defects in bacteria attributed to accumulation of frameshifting during translation (6). In humans, mutations within the gene coding for the 2-thiouridylase TrmU, responsible for the sulfur insertion step, has been associated with acute in...

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Section: Levels Of Expression Of Mnma Affects Abundance Of Smentioning

confidence: 58%

“…In previous work, we and others showed that sufS is adjacent to its sulfur acceptor gene, sufU (17,18), coding for a zinc-dependent sulfur transfer protein (19). Both proteins are involved in the formation of Fe-S clusters.…”

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confidence: 99%

Abbreviated Pathway for Biosynthesis of 2-Thiouridine in Bacillus subtilis

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Santos

2015

J Bacteriol

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“…SufS is a cysteine desulfurase that catalyzes the removal of elemental sulfur from cysteine, producing alanine and a SufS-bound persulfide (15). The persulfide is transferred to SufU, which is a sulfur transfer protein that provides the sulfur to SufBCD (16). After synthesis, the Fe-S cluster is transferred directly to either an apoprotein or an Fe-S cluster carrier that traffics the cofactor to the target apoprotein (11,17).…”

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confidence: 99%

The Suf Iron-Sulfur Cluster Biosynthetic System Is Essential in Staphylococcus aureus, and Decreased Suf Function Results in Global Metabolic Defects and Reduced Survival in Human Neutrophils

et al. 2017

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Staphylococcus aureus remains a causative agent for morbidity and mortality worldwide. This is in part a result of antimicrobial resistance, highlighting the need to uncover novel antibiotic targets and to discover new therapeutic agents. In the present study, we explored the possibility that iron-sulfur (Fe-S) cluster synthesis is a viable antimicrobial target. RNA interference studies established that Suf (sulfur mobilization)-dependent Fe-S cluster synthesis is essential in S. aureus. We found that sufCDSUB were cotranscribed and that suf transcription was positively influenced by sigma factor B. We characterized an S. aureus strain that contained a transposon inserted in the intergenic space between sufC and sufD (sufD*), resulting in decreased transcription of sufSUB. Consistent with the transcriptional data, the sufD* strain had multiple phenotypes associated with impaired Fe-S protein maturation. They included decreased activities of Fe-S cluster-dependent enzymes, decreased growth in media lacking metabolites that require Fe-S proteins for synthesis, and decreased flux through the tricarboxylic acid (TCA) cycle. Decreased Fe-S cluster synthesis resulted in sensitivity to reactive oxygen and reactive nitrogen species, as well as increased DNA damage and impaired DNA repair. The sufD* strain also exhibited perturbed intracellular nonchelated Fe pools. Importantly, the sufD* strain did not exhibit altered exoprotein production or altered biofilm formation, but it was attenuated for survival upon challenge by human polymorphonuclear leukocytes. The results presented are consistent with the hypothesis that Fe-S cluster synthesis is a viable target for antimicrobial development.KEYWORDS iron, sulfur, cluster, Staphylococcus aureus, Suf, neutrophil S taphylococcus aureus is a human commensal that causes morbidity and mortality worldwide. While it is responsible for low-morbidity maladies, such as folliculitis, it is also capable of causing fatal afflictions, such as endocarditis, bacteremia, and toxic shock syndrome (1, 2). Bacterial antibiotic resistance continues to increase and to be problematic. Infections caused by antibiotic-resistant S. aureus result in increased mortality, increased stress on the health care system, and an increased financial burden (3, 4). Current FDA-approved antibacterials target a limited number of metabolic processes (5). Developing antibacterials that target alternate processes would expand treatment options and aid in multidrug therapy. These facts highlight the need for

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“…Another protein belonging to the SUF system is the Zn-dependent SufU [57], which is absent in the Gram-negative bacteria such as E. coli . SufU, a homolog of IscU, is able to complement SufE, as it happens in the case of Bacillus subtillis, Enterococcus faecalis, Thermatoga maritima and various mycobacteria [58–61].…”

Section: Fe–s Cluster Machineries: a Brief Overviewmentioning

confidence: 99%

Fe–S cluster assembly in the supergroup Excavata

Peña-Diaz

Lukeš

2018

J Biol Inorg Chem

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The majority of established model organisms belong to the supergroup Opisthokonta, which includes yeasts and animals. While enlightening, this focus has neglected protists, organisms that represent the bulk of eukaryotic diversity and are often regarded as primitive eukaryotes. One of these is the “supergroup” Excavata, which comprises unicellular flagellates of diverse lifestyles and contains species of medical importance, such as Trichomonas, Giardia, Naegleria, Trypanosoma and Leishmania. Excavata exhibits a continuum in mitochondrial forms, ranging from classical aerobic, cristae-bearing mitochondria to mitochondria-related organelles, such as hydrogenosomes and mitosomes, to the extreme case of a complete absence of the organelle. All forms of mitochondria house a machinery for the assembly of Fe–S clusters, ancient cofactors required in various biochemical activities needed to sustain every extant cell. In this review, we survey what is known about the Fe–S cluster assembly in the supergroup Excavata. We aim to bring attention to the diversity found in this group, reflected in gene losses and gains that have shaped the Fe–S cluster biogenesis pathways.

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Fe-S Cluster Biogenesis in Gram-Positive Bacteria: SufU Is a Zinc-Dependent Sulfur Transfer Protein

Cited by 68 publications

References 42 publications

Abbreviated Pathway for Biosynthesis of 2-Thiouridine in Bacillus subtilis

Abbreviated Pathway for Biosynthesis of 2-Thiouridine in Bacillus subtilis

The Suf Iron-Sulfur Cluster Biosynthetic System Is Essential in Staphylococcus aureus, and Decreased Suf Function Results in Global Metabolic Defects and Reduced Survival in Human Neutrophils

Fe–S cluster assembly in the supergroup Excavata

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